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2618 Loss of FXR Signaling Promotes Chronic Liver Injury in Sickle Cell Disease

Program: Oral and Poster Abstracts
Session: 113. Hemoglobinopathies, Excluding Thalassemia—Basic and Translational Science: Poster III
Hematology Disease Topics & Pathways:
Anemias, sickle cell disease, Diseases, Hemoglobinopathies, Biological Processes, immune mechanism, inflammation, signal transduction
Monday, December 7, 2020, 7:00 AM-3:30 PM

Ravi Vats, MSc1, Enrico M Novelli, M.D., M.S.2, Mark T. Gladwin, MD3, Prithu Sundd, PhD1 and Tirthadipa Pradhan4

1Pittsburgh Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA
2Heart, Lung and Blood Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA
3University of Pittsburgh, Pittsburgh, PA
4University of Pittsburgh, Pittsburgh

Hepatic crisis is an emergent complication affecting sickle cell disease (SCD) patients, however, the molecular mechanism of sickle cell hepatobiliary crisis remains poorly understood. We have used intravital imaging to show that sinusoidal ischemia occurs in the liver of transgenic-humanized SCD mice under basal condition. SCD mice manifested progressive hepatomegaly, liver injury and hyperbilirubinemia. RNA-sequence analysis identified dysregulation of genes encoding proteins responsible for fibrosis, bile acid synthesis, and bile transport in the SCD mice liver. Live injury was the result of NF-κB-dependent inhibition of FXR signaling and its downstream targets in hepatocytes, leading to loss of canalicular bile transport and bile metabolism. Blocking NF-κB activation rescued FXR-signaling, ameliorated liver injury and resolved sinusoidal ischemia in SCD mice. Moreover, administration of FXR agonist (GW4064) also ameliorated liver injury seen in SCD mice. These findings are the first to identify that FXR-dependent impaired bile secretion promotes intrahepatic bile accumulation, which contributes to hepatobiliary injury of SCD. Improved understanding of these pathways could potentially benefit the development of new therapies to treat sickle cell hepatic crisis.

Disclosures: Gladwin: Novartis: Consultancy; Globin Solutions: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: Not relevant to SCD; Bayer: Consultancy, Research Funding; Actelion: Consultancy; Pfizer: Consultancy.

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